tbuckley/cabot-search huggingface dataset:
Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant
Authors: Motaharehsadat Heydarian, Prajakta Oak, Xin Zhang, Nona Kamgari, Alida Kindt, Markus Koschlig, Tina Pritzke, Erika Gonzalez-Rodriguez, Kai Förster, Rory E Morty, Friederike Häfner, Christoph Hübener, Andreas W Flemmer, Ali Oender Yildirim, Deepti Sudheendra, Xuefei Tian, Agnese Petrera, Holger Kirsten, Peter Ahnert, Nick Morrell, Tushar J Desai, Jennifer Sucre, Edda Spiekerkoetter, Anne Hilgendorff
Journal: Thorax (2022)

Introduction Chronic lung disease, that is, bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and develops as a consequence of the misguided formation of the gas-exchange area undergoing prenatal and postnatal injury. Subsequent vascular disease and its progression into pulmonary arterial hypertension critically determines long-term outcome in the BPD infant but lacks identification of early, disease-defining changes. Methods We link impaired bone morphogenetic protein (BMP) signalling to the earliest onset of vascular pathology in the human preterm lung and delineate the specific effects of the most prevalent prenatal and postnatal clinical risk factors for lung injury mimicking clinically relevant conditions in a multilayered animal model using wild-type and transgenic neonatal mice. Results We demonstrate (1) the significant reduction in BMP receptor 2 (BMPR2) expression at the onset of vascular pathology in the lung of preterm infants, later mirrored by reduced plasma BMP protein levels in infants with developing BPD, (2) the rapid impairment (and persistent change) of BMPR2 signalling on postnatal exposure to hyperoxia and mechanical ventilation, aggravated by prenatal cigarette smoke in a preclinical mouse model and (3) a link to defective alveolar septation and matrix remodelling through platelet derived growth factor-receptor alpha deficiency. In a treatment approach, we partially reversed vascular pathology by BMPR2-targeted treatment with FK506 in vitro and in vivo. Conclusion We identified impaired BMP signalling as a hallmark of early vascular disease in the injured neonatal lung while outlining its promising potential as a future biomarker or therapeutic target in this growing, high-risk patient population.
Fasting induces a highly resilient deep quiescent state in muscle stem cells via ketone body signaling
Authors: Daniel I. Benjamin, Pieter Both, Joel S. Benjamin, Christopher W. Nutter, Jenna H. Tan, Jengmin Kang, Leo A. Machado, Julian D.D. Klein, Antoine de Morree, Soochi Kim, Ling Liu, Hunter Dulay, Ludovica Feraboli, Sharon M. Louie, Daniel K. Nomura, Thomas A. Rando
Journal: Cell Metabolism (2022)
Advanced basal cell carcinoma: What dermatologists need to know about diagnosis
Authors: Andrew C. Krakowski, Farhaan Hafeez, Alan Westheim, Eva Y. Pan, Melissa Wilson
Journal: Journal of the American Academy of Dermatology (2022)

Basal cell carcinoma (BCC) is the most common human cancer, with approximately 3.6 million cases diagnosed each year. About 2000 deaths annually in the United States are attributed to basal and squamous cell skin cancers. There is a direct link between ultraviolet exposure and the development of BCC, as UV exposure damages DNA and induces mutations in tumor suppressor genes. Aberrations in the hedgehog pathway can also result in BCC, highlighted by the fact that most cases of sporadic BCCs have been found to have mutations in different genes involved in the hedgehog pathway. There are several genetic syndromes that are associated with BCCs, including basal cell nevus syndrome, xeroderma pigmentosum, Bazex-Dupré-Christol syndrome, Rombo syndrome, and Oley syndrome. Other risk factors include age, male gender, occupational hazards, radiation, and immunosuppression. BCCs are not typically staged but are instead stratified by their risk of recurring or metastasizing. Locally advanced BCCs are those tumors that are not amenable to surgery or radiation therapy.
Combined Sewer Overflows and Gastrointestinal Illness in Atlanta, 2002–2013: Evaluating the Impact of Infrastructure Improvements
Authors: Alyssa G. Miller, Stefanie Ebelt, Karen Levy
Journal: Environmental Health Perspectives (2022)

Combined sewer overflows (CSOs) discharge untreated sewage into surface and recreational water, often following heavy precipitation. Given projected increases in frequency and intensity of precipitation due to climate change, it is important to understand the health impacts of CSOs and mediating effects of sewerage systems.In this study we estimate associations of CSO events and emergency department (ED) visits for gastrointestinal (GI) illness among City of Atlanta, Georgia, residents and explore how these associations vary with sewerage improvements.We estimate associations using Poisson generalized linear models, controlling for time trends. We categorized CSOs by overflow volume and assessed effects of CSO events prior to ED visits with 1-, 2- and 3-wk lags. Similarly, we evaluated effects of weekly cumulative precipitation greater than the 90th percentile at the same lags. We also evaluated effect modification by ZIP Code Tabulation Area (ZCTA)-level poverty and infrastructure improvement period using interaction terms.Occurrence of a large volume CSO in the previous week was associated with a 9% increase in daily ED visits for GI illness. We identified significant interaction by ZCTA-level poverty, with stronger CSO-GI illness associations in low than high poverty areas. Among areas with low poverty, we observed associations at 1-wk and longer lags, following both large and lower volume CSO events. We did not observe significant interaction by infrastructure improvement period for CSO- nor precipitation-GI illness associations; however, the number of CSO events decreased from 2.31 per week before improvements to 0.49 after improvements.Our findings suggest that CSOs contribute to acute GI illness burden in Atlanta and that the magnitude of this risk may be higher among populations living in areas of low poverty. We did not find a protective effect of sewerage system improvements. Nonetheless, observed reductions in CSO frequency may lower the absolute burden of GI illness attributable to these events. https://doi.org/10.1289/EHP10399.
Assessing the effect of non-pharmaceutical interventions on COVID-19 transmission in Spain, 30 August 2020 to 31 January 2021
Authors: David García-García, Rafael Herranz-Hernández, Ayelén Rojas-Benedicto, Inmaculada León-Gómez, Amparo Larrauri, Marina Peñuelas, María Guerrero-Vadillo, Rebeca Ramis, Diana Gómez-Barroso
Journal: Eurosurveillance (2022)

BackgroundAfter a national lockdown during the first wave of the COVID-19 pandemic in Spain, regional governments implemented different non-pharmaceutical interventions (NPIs) during the second wave.AimTo analyse which implemented NPIs significantly impacted effective reproduction number (Rt) in seven Spanish provinces during 30 August 2020-31 January 2021.MethodsWe coded each NPI and levels of stringency with a 'severity index' (SI) and computed a global SI (mean of SIs per six included interventions). We performed a Bayesian change point analysis on the Rt curve of each province to identify possible associations with global SI variations. We fitted and compared several generalised additive models using multimodel inference, to quantify the statistical effect on Rt of the global SI (stringency) and the individual SIs (separate effect of NPIs).ResultsThe global SI had a significant lowering effect on the Rt (mean: 0.16 ± 0.05 units for full stringency). Mandatory closing times for non-essential businesses, limited gatherings, and restricted outdoors seating capacities (negative) as well as curfews (positive) were the only NPIs with a significant effect. Regional mobility restrictions and limited indoors seating capacity showed no effect. Our results were consistent with a 1- to 3-week-delayed Rt as a response variable.ConclusionWhile response measures implemented during the second COVID-19 wave contributed substantially to a decreased reproduction number, the effectiveness of measures varied considerably. Our findings should be considered for future interventions, as social and economic consequences could be minimised by considering only measures proven effective.
Abstract A019: Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential (CHIP) using fluctuating methylation clocks
Authors: Ryan O. Schenck, Niels Asger Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, Alexander R.A. Anderson
Journal: Cancer Research (2022)

Abstract Clonal hematopoiesis (CH), such as clonal hematopoiesis of indeterminant potential (CHIP), is diagnosed based on somatic genomic alterations in the absence of hematologic malignancy. At present, CHIP is diagnosed using peripheral blood, where putative driver point mutations and small insertions/deletions whose variant allele frequency is greater or equal to two percent. Generally, the prevalence of CH increases as an individual ages and conveys a risk for progression to a malignancy. CH is thought to be driven by the underlying hematopoietic stem cells of an unknown quantity, with estimates in the literature for stem cell numbers differing by orders of magnitude. Previously, we developed a method using fluctuating CpG (fCpG) sites to serve as a fluctuating methylation clock to uncover stem cell dynamics in glandular tissues and orthogonally validated our method using publicly available datasets of human blood from normal cohorts and malignant cohorts. Here we expand on this work by presenting 38 new patients with distinct VAF groups from 1-2% VAF up to greater than 10% VAF for putative drivers with corresponding DNA methylation profiles using the Illumina EPIC array platform. We identify fCpG from our normal and CHIP cohorts to train and validate a machine learning approach that allows us to diagnose CHIP without DNA sequencing. Importantly, our approach allows for the identification of patients who may have CH driven by structural variants such as copy number alterations. We use this method to evaluate two publicly available methylation datasets of reportedly normal patients (n=656 and n=732) showing that evidence of CHIP can be found in 19% and 29% of these datasets, respectively. We then evaluate copy number differences in burden within our CHIP cohort and these newly identified CHIP cohorts. Using a mechanistic model of hematopoietic stem cells containing fCpGs we examine the temporal dynamics of competing founder CHIP drivers and the number of stem cells in the hematopoietic stem cell compartment. Citation Format: Ryan O. Schenck, Niels Asger Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, Alexander R.A. Anderson. Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential (CHIP) using fluctuating methylation clocks [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A019.
LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade
Authors: Amber Hickman, Joost Koetsier, Trevin Kurtanich, Michael C. Nielsen, Glenn Winn, Yunfei Wang, Salah-Eddine Bentebibel, Leilei Shi, Simone Punt, Leila Williams, Cara Haymaker, Charles B. Chesson, Faisal Fa’ak, Ana L. Dominguez, Richard Jones, Isere Kuiatse, Amy R. Caivano, Sayadeth Khounlo, Navin D. Warier, Upendra Marathi, Robert V. Market, Ronald J. Biediger, John W. Craft, Patrick Hwu, Michael A. Davies, Darren G. Woodside, Peter Vanderslice, Adi Diab, Willem W. Overwijk, Yared Hailemichael
Journal: Journal of Clinical Investigation (2022)

The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti-programmed death 1-resistant (anti-PD-1-resistant) tumors, whereas combinatorial treatment with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) increased CD8+ Teff intratumoral sequestration and synergized in cooperation with neutrophils in inducing cancer regression. 7HP349 intratumoral CD8+ Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression as possibly improving the likelihood or response to anti-CTLA-4 therapies. Our results provide a proof-of-principle demonstration that LFA-1 activation could convert a T cell-exclusionary TME to a T cell-enriched TME through mechanisms involving cooperation with innate immune cells.
Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma
Authors: Crismita Dmello, Aarón Sonabend, Victor A. Arrieta, Daniel Y. Zhang, Deepak Kanojia, Li Chen, Andrew Gould, Jiangshan Zhang, Seong Jae Kang, Jan Winter, Craig Horbinski, Christina Amidei, Balázs Győrffy, Alex Cordero, Catalina Lee Chang, Brandyn Castro, Patrick Hsu, Atique U. Ahmed, Maciej S. Lesniak, Roger Stupp, Adam M. Sonabend
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Paclitaxel (PTX) is one of the most potent and commonly used chemotherapies for breast and pancreatic cancer. Several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood–brain barrier for glioblastomas. Despite the widespread use of PTX for breast cancer, and the initiative to repurpose this drug for gliomas, there are no predictive biomarkers to inform which patients will likely benefit from this therapy. Experimental Design: To identify predictive biomarkers for susceptibility to PTX, we performed a genome-wide CRISPR knockout (KO) screen using human glioma cells. The genes whose KO was most enriched in the CRISPR screen underwent further selection based on their correlation with survival in the breast cancer patient cohorts treated with PTX and not in patients treated with other chemotherapies, a finding that was validated on a second independent patient cohort using progression-free survival. Results: Combination of CRISPR screen results with outcomes from patients with taxane-treated breast cancer led to the discovery of endoplasmic reticulum (ER) protein SSR3 as a putative predictive biomarker for PTX. SSR3 protein levels showed positive correlation with susceptibility to PTX in breast cancer cells, glioma cells, and in multiple intracranial glioma xenografts models. KO of SSR3 turned the cells resistant to PTX while its overexpression sensitized the cells to PTX. Mechanistically, SSR3 confers susceptibility to PTX through regulation of phosphorylation of ER stress sensor IRE1α. Conclusions: Our hypothesis generating study showed SSR3 as a putative biomarker for susceptibility to PTX, warranting its prospective clinical validation.
An immunomodulatory polypeptide hydrogel for osteochondral defect repair
Authors: Meng Yang, Zheng-Chu Zhang, Fu-Zhen Yuan, Rong-Hui Deng, Xin Yan, Feng-Biao Mao, You-Rong Chen, Hua Lu, Jia-Kuo Yu
Journal: Bioactive Materials (2022)

Osteochondral injury is a common and frequent orthopedic disease that can lead to more serious degenerative joint disease. Tissue engineering is a promising modality for osteochondral repair, but the implanted scaffolds are often immunogenic and can induce unwanted foreign body reaction (FBR). Here, we prepare a polypept(o)ide-based PAA-RGD hydrogel using a novel thiol/thioester dual-functionalized hyperbranched polypeptide P(EG3Glu-co-Cys) and maleimide-functionalized polysarcosine under biologically benign conditions. The PAA-RGD hydrogel shows suitable biodegradability, excellent biocompatibility, and low immunogenicity, which together lead to optimal performance for osteochondral repair in New Zealand white rabbits even at the early stage of implantation. Further in vitro and in vivo mechanistic studies corroborate the immunomodulatory role of the PAA-RGD hydrogel, which induces minimum FBR responses and a high level of polarization of macrophages into the immunosuppressive M2 subtypes. These findings demonstrate the promising potential of the PAA-RGD hydrogel for osteochondral regeneration and highlight the importance of immunomodulation. The results may inspire the development of PAA-based materials for not only osteochondral defect repair but also various other tissue engineering and bio-implantation applications.
Self‐Confirming Magnetosomes for Tumor‐Targeted <i>T</i><sub>1</sub><i>/T</i><sub>2</sub> Dual‐Mode MRI and MRI‐Guided Photothermal Therapy
Authors: Gexuan Jiang, Di Fan, Jiesheng Tian, Zhichu Xiang, Qiaojun Fang
Journal: Advanced Healthcare Materials (2022)

Nanomaterials as T1 /T2 dual-mode magnetic resonance imaging (MRI) contrast agents have great potential in improving the accuracy of tumor diagnosis. Applications of such materials, however, are limited by the complicated chemical synthesis process and potential biosafety issues. In this study, the biosynthesis of manganese (Mn)-doped magnetosomes (MagMn) that not only can be used in T1 /T2 dual-mode MR imaging with self-confirmation for tumor detection, but also improve the photothermal conversion efficiency for MRI-guided photothermal therapy (PTT) is reported. The MagMn nanoparticles (NPs) are naturally produced through the biomineralization of magnetotactic bacteria by doping Mn into the ferromagnetic iron oxide crystals. In vitro and in vivo studies demonstrated that targeting peptides functionalized MagMn enhanced both T1 and T2 MRI signals in tumor tissue and significantly inhibited tumor growth by the further MRI-guided PTT. It is envisioned that the biosynthesized multifunctional MagMn nanoplatform may serve as a potential theranostic agent for cancer diagnosis and treatment.
Intravenous iron supplement for iron deficiency in patients with severe aortic stenosis scheduled for transcatheter aortic valve implantation: results of the <scp>IIISAS</scp> randomised trial
Authors: Anette B. Kvaslerud, Sara Bardan, Kristoffer Andresen, Sophie F. Kløve, Morten W. Fagerland, Thor Edvardsen, Lars Gullestad, Kaspar Broch
Journal: European Journal of Heart Failure (2022)
Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer
Authors: Beshara Sheehan, Antje Neeb, Lorenzo Buroni, Alec Paschalis, Ruth Riisnaes, Bora Gurel, Veronica Gil, Susana Miranda, Mateus Crespo, Christina Guo, Juan Jiménez Vacas, Ines Figueiredo, Ana Ferreira, Jon Welti, Wei Yuan, Suzanne Carreira, Adam Sharp, Johann de Bono
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Prostate-specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)–PSMA-617 are affecting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression, raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies and therefore hypothesized that DNA damage upregulates PSMA expression. Experimental Design: To test this relationship between PSMA and DNA damage we conducted a screen of 147 anticancer agents (NCI/NIH FDA-approved anticancer “Oncology Set”) and treated tumor cells with repeated ionizing irradiation. Results: The topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, were identified from the screen to upregulate PSMA protein expression in castration-resistant LNCaP95 cells; this result was validated in vitro in LNCaP, LNCaP95, and 22Rv1 cell lines and in vivo using an mCRPC patient-derived xenograft model CP286 identified to have heterogeneous PSMA expression. As double-strand DNA break induction by topoisomerase-2 inhibitors upregulated PSMA, we next studied the impact of ionizing radiation on PSMA expression; this also upregulated PSMA protein expression in a dose-dependent fashion. Conclusions: The results presented herein are the first, to our knowledge, to demonstrate that PSMA is upregulated in response to double-strand DNA damage by anticancer treatment. These data support the study of rational combinations that maximize the antitumor activity of PSMA-targeted therapeutic strategies by upregulating PSMA.
How Caring for Patients Could Change in a Post–<i>Roe v Wade</i> US
Authors: Rita Rubin, Jennifer Abbasi, Melissa Suran
Journal: JAMA (2022)

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Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL
Authors: Caroline Diorio, Ryan Murray, Mark Naniong, Luis Barrera, Adam Camblin, John Chukinas, Lindsey Coholan, Aaron Edwards, Tori Fuller, Claudia Gonzales, Stephan A. Grupp, Alden Ladd, Melissa Le, Angelica Messana, Faith Musenge, Haley Newman, Yeh-Chuin Poh, Henry Poulin, Theresa Ryan, Rawan Shraim, Sarah K. Tasian, Tiffaney Vincent, Lauren Young, Yingying Zhang, Giuseppe Ciaramella, Jason Gehrke, David T. Teachey
Journal: Blood (2022)

Allogeneic chimeric antigen receptor T-cell (CART) therapies require multiple gene edits to be clinically tractable. Most allogeneic CARTs have been created using gene editing techniques that induce DNA double-stranded breaks (DSBs), resulting in unintended on-target editing outcomes with potentially unforeseen consequences. Cytosine base editors (CBEs) install C•G to T•A point mutations in T cells, with between 90% and 99% efficiency to silence gene expression without creating DSBs, greatly reducing or eliminating undesired editing outcomes following multiplexed editing as compared with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). Using CBE, we developed 7CAR8, a CD7-directed allogeneic CART created using 4 simultaneous base edits. We show that CBE, unlike CRISPR-Cas9, does not impact T-cell proliferation, lead to aberrant DNA damage response pathway activation, or result in karyotypic abnormalities following multiplexed editing. We demonstrate 7CAR8 to be highly efficacious against T-cell acute lymphoblastic leukemia (T-ALL) using multiple in vitro and in vivo models. Thus, CBE is a promising technology for applications requiring multiplexed gene editing and can be used to manufacture quadruple-edited 7CAR8 cells, with high potential for clinical translation for relapsed and refractory T-ALL.